Noonan Syndrome
Noonan syndrome is an autosomal dominant RASopathy with an incidence of about 1 in 1,000 to 2,500 live births. It is caused by activating variants in the RAS-MAPK signalling pathway.
PTPN11 variants account for about 50%, SOS1 about 10 to 13%, RAF1 about 5%, RIT1 about 5%, with others in KRAS, NRAS, BRAF, MAP2K1, LZTR1, SOS2, and others.
About 60 to 75% of cases are de novo. The condition has the same pathway as cardiofaciocutaneous, Costello and Noonan syndrome with multiple lentigines (LEOPARD).
- Facies: hypertelorism, down slanting palpebral fissures, ptosis, low set posteriorly rotated ears with thick helix, a deeply grooved philtrum, webbed neck with low posterior hairline; facial features sharpen in childhood and soften in adulthood
- Cardiac (about 80 to 90%): pulmonary valve stenosis (50 to 60%, with dysplastic valve), hypertrophic cardiomyopathy (about 20%; especially with RAF1 and RIT1 variants; may present in infancy), atrial septal defect, and coarctation
- Short stature (final height about 162 cm in men and 153 cm in women), with delayed puberty and bone age
- Chest deformity (pectus carinatum superiorly and excavatum inferiorly)
- Bleeding diathesis (about 50 to 65%): factor XI deficiency, platelet dysfunction, and others, with easy bruising and surgical bleeding
- Cryptorchidism (about 60 to 80% of males), with reduced fertility in males
- Developmental and learning problems (about 20 to 30% have intellectual disability), speech delay, and feeding difficulty in infancy
- Lymphatic dysplasia (lymphoedema, chylothorax, hydrops), eye problems (strabismus, refractive errors, amblyopia), hearing loss, myeloproliferative disorders (juvenile myelomonocytic leukaemia, particularly with PTPN11 mutations), and increased risk of other cancers
- Clinical diagnosis uses van der Burgt criteria (characteristic facies plus one major or two minor criteria) and is confirmed by multigene panel testing (RASopathy panel) or exome sequencing; a negative test does not exclude the clinical diagnosis.
- Baseline evaluation: echocardiography and ECG at diagnosis; full blood count, coagulation screen (prothrombin time, activated partial thromboplastin time), factor levels (VIII, XI, XII, von Willebrand), and platelet function before surgery; renal ultrasound; audiology and ophthalmology; growth and developmental assessment.
- Cardiac: paediatric cardiology follow up; balloon pulmonary valvuloplasty has limited success with dysplastic valves, and surgery may be needed; hypertrophic cardiomyopathy managed with beta blockers (propranolol 1 to 4 mg/kg/day or atenolol) and surgical myectomy for outflow tract obstruction; avoid digoxin and inotropes in hypertrophic cardiomyopathy. Sudden death and heart failure risk is highest in infants with RAF1 variants.
- Growth hormone: recombinant GH 0.033 to 0.066 mg/kg/day (about 0.23 to 0.46 mg/kg/week) improves height velocity; monitor for cardiac hypertrophy (echocardiography at baseline and annually) and avoid in significant hypertrophic cardiomyopathy.
- Bleeding: preoperative haematology consultation, tranexamic acid, desmopressin, factor replacement, and avoid aspirin and NSAIDs where a defect is identified.
- Cryptorchidism: orchidopexy at 6 to 12 months.
- Development: early intervention, speech therapy, and educational support.
- Feeding difficulty: high calorie formula, nasogastric feeding, and gastrostomy as needed.
- Oncology awareness: monitor for leukaemia and solid tumours (neuroblastoma, rhabdomyosarcoma); full blood count if unexplained symptoms.
- Genetic counselling: 50% recurrence risk when a parent is affected; examine parents (subtle features).
- MEK inhibitors (trametinib, selumetinib) are being studied for severe hypertrophic cardiomyopathy and lymphatic disease.
